The estrogen-immune axis: A key regulator of behavioural inflexibility

Aberrant insulin signalling was recently identified as a causative mechanism of Obsessive-Compulsive Disorder (OCD). Indeed, TALLYHO/JngJ mouse models of Type 2 diabetes are compulsive and anxious, with treatment with the Type 2 diabetes drug metformin generating partial rescue. Here, we aimed to establish the mechanisms behind this insulin-behavioural axis via proteomic analysis of brain and blood. Additionally, data from Genome-Wide Association studies (GWAS) of relevant disorders were compared using Ingenuity Pathway Analysis (IPA) (Qiagen). IPA analysis of proteomic results showed dysregulated immunity in TALLYHO/JngJ mice. Based on these findings, pairwise analyses were performed across GWAS studies of inflammatory vs behaviourally inflexible disorders to identify recurring upstream mechanisms. This identified the female sex hormone beta-estradiol (p<0.01). Furthermore, comparison across aforementioned human GWAS and mouse proteomic analyses indicated that beta-estradiol regulation of Interleukin-1, a major proinflammatory cytokine, is a converging mechanism. This was further confirmed as an enriched mechanism in mass spectrometry of TALLYHO/JngJ mice. Mass spectrometry analysis of brain and blood of these mice with and without treatment with metformin confirms estrogen signalling as a major therapeutic mechanism (p=7.9E-39). We conclude that beta-estradiol-immune dysregulation is a key mechanism underlying behavioural inflexibility in TALLYHO/JngJ mice.